A Prophylactic Trial of Omega-3 Polyunsaturated Fatty Acids in Bipolar Disorder

Bipolar Disorder is a chronic disabling psychiatric disorder characterized by recurrent episodes of mania or hypomania and depression. Bipolar Disorder can be separated into bipolar I and bipolar II disorders with bipolar I disorder characterizing individuals who have episodes of mania and depression, and bipolar II disorder characterizing individuals who have episodes of depression with periods of hypomania, but not mania. Bipolar Disorder has an estimated prevalence of approximately 1% and a roughly equal gender ratio. Treatment of bipolar disorder is predominantly by pharmacological means with probably the most evidence still supporting the role of lithium both for the treatment of bipolar disorder and prophylaxis of further episodes (particularly (hypo)manic episodes.

A number of other standard mood stabiliser agents are often utilised including sodium valproate, carbamazepine and lamotrigine. Over the last 10 years, a number of antipsychotic agents have attained a licence for the treatment of bipolar disorder including olanzapine, quetiapine, asenapine and aripiprazole. All of these treatments are associated with significant adverse effects. For example, lithium has been associated with hypothyroidism and diabetes insipidus, interacts with a variety of other agents including non-steroidal anti-inflammatory drugs, diuretics and requires careful blood monitoring to ensure that the individuals blood level is within a therapeutic range (to avoid toxicity or subclinical treatment). Sodium Valproate is associated with several adverse effects; principal amongst these is teratogenesis in pregnancy, but also alopecia and a hand tremor. Carbamazepine is associated with blood dyscrasias and hyponatraemia and interacts with many medications. Lamotrigine has been utilised for the treatment of bipolar depression, however it can take several months of treatment before one reaches therapeutic doses, and severe skin rashes occasionally occur. In relation to the antipsychotic agents, olanzapine is associated with significant weight gain, somnolence and metabolic syndrome, quetiapine is associated with hypotension and somnolence, aripiprazole is associated with akathisia and asenapine is associated with dizziness and somnolence. Whilst psychotherapy has demonstrated some benefit for the treatment of bipolar depression, to date, the role of psychotherapy for the management of (hypo)mania remains limited.

The putative role of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) principally eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the treatment of mood disorders has been supported by a wide variety of epidemiological observations, tissue compositional comparisons, clinical and treatment studies. For example, cross-national studies have found a substantially higher incidence of depression, suicide, and bipolar disorder in cultures with low omega-3 PUFA intake (due to low levels of fish consumption) with low levels of fish consumption also independently associated with symptoms of depression. Lower concentrations of both EPA and DHA have been found in red blood cells of depressed individuals compared to healthy controls, and the ratio of EPA to the omega-6 PUFA arachidonic acid (AA) has been demonstrated both in depression and in mania. The most specific evidence for central tissue compositional deficits is the finding of lower DHA in the post-mortem orbitofrontal cortex of patients with both major depressive disorder and bipolar disorder.

Several randomised controlled trials have also demonstrated a benefit for omega-3 PUFAs in depression, although these findings are not universal and meta-analyses have noted substantial heterogeneity in these findings. Although there have been multiple treatment trials examining the putative antidepressant effect of omega-3 PUFAs in recurrent depressive disorder, we are aware of only six randomised double-blind placebo-controlled trials to date that have investigated if omega-3 PUFAs have a therapeutic role in bipolar disorder. In these trials, results have been contradictory with two studies demonstrating a benefit for omega-3 PUFAs compared to placebo, with both of these trials demonstrating a reduction in depressive but not manic symptoms. with one study using high dose EPA (6.2g) and DHA (3.4g) for a period of 16 weeks, and another using lower formulations of EPA alone at doses of 1g or 2g for a period of 12 weeks. In relation to the five negative trials to date; DHA alone (2g) was administered to a small cohort of euthymic bipolar individuals (n=10; 6 = DHA, 4 = placebo) over a 52 week period in one study. Another study administered high dose EPA (6g) however, the drop-out rate was high at 54%. Two trials administered alpha-linolenic acid (ALA) (the parent omega-3 PUFA) or a mixture of PUFAs (3g EPA and 2g DHA) and pyrimidine cytidine (n=15), with no benefit noted. One final study was presented in the form of a letter to the editor and conducted in a small cohort of 15 individuals with minimal data provided.

Therefore, it is unclear if omega-3 PUFAs have a therapeutic role in bipolar disorder. Studies to date have utilised a variety of PUFA formulations, for short time periods and have included either modest numbers or have had high drop-out rates.